Compounds useful for treating allergic and inflammatory diseases

ABSTRACT

Novel cyclohexane-ylidene derivatives of formula (I) are described. These compounds inhibit the production of Tumor Necrosis Factor and are useful in the treatment of disease states mediated or exacerbated by TNF production. These compounds are also useful in the mediation or inhibition of enzymatic or catalytic activity of phosphodiesterase IV and are therefore useful in the treatment of disease states in need of mediation or inhibition thereof. ##STR1##

This is a National Stage Application of PCT/US93/01988 filed 5 March1993 and published as WO93/19747 which is a continuation-in-part of U.S.application Ser. No. 07/968,760 filed Oct. 30, 1992, now abandoned;which is a continuation-in-part of U.S. application Ser. No. 07/862,112filed Apr. 2, 1992, now abandoned.

FIELD OF INVENTION

The present invention relates to novel compounds, pharmaceuticalcompositions containing these compounds, and their use in treatingallergic and inflammatory diseases and for inhibiting the production ofTumor Necrosis Factor (TNF).

BACKGROUND OF THE INVENTION

Bronchial asthma is a complex, multifactorial disease characterized byreversible narrowing of the airway and hyperreactivity of therespiratory tract to external stimuli.

Identification of novel therapeutic agents for asthma is made difficultby the fact that multiple mediators are responsible for the developmentof the disease. Thus, it seems unlikely that eliminating the effects ofa single mediator will have a substantial effect on all three componentsof chronic asthma. An alternative to the "mediator approach" is toregulate the activity of the cells responsible for the pathophysiologyof the disease.

One such way is by elevating levels of cAMP (adenosine cyclic3',5'-monophosphate). Cyclic AMP has been shown to be a second messengermediating the biologic responses to a wide range of hormones,neurotransmitters and drugs; [Krebs Endocrinology Proceedings of the 4thInternational Congress Excerpta Medica, 17-29, 1973]. When theappropriate agonist binds to specific cell surface receptors, adenylatecyclase is activated, which converts Mg⁺² -ATP to cAMP at an acceleratedrate.

Cyclic AMP modulates the activity of most, if not all, of the cells thatcontribute to the pathophysiology of extrinsic (allergic) asthma. Assuch, an elevation of cAMP would produce beneficial effects including: 1) airway smooth muscle relaxation, 2) inhibition of mast cell mediatorrelease, 3) suppression of neutrophil degranulation, 4) inhibition ofbasophil degranulation, and 5) inhibition of monocyte and macrophageactivation. Hence. compounds that activate adenylate cyclase or inhibitphosphodiesterase should be effective in suppressing the inappropriateactivation of airway smooth muscle and a wide variety of inflammatorycells. The principal cellular mechanism for the inactivation of cAMP ishydrolysis of the 3'-phosphodiester bond by one or more of a family ofisozymes referred to as cyclic nucleotide phosphodiesterases (PDEs).

It has now been shown that a distinct cyclic nucleotidephosphodiesterase (PDE) isozyme, PDE IV, is responsible for cAMPbreakdown in airway smooth muscle and inflammatory cells. [Torphy,"Phosphodiesterase Isozymes: Potential Targets for Novel AntiasthmaticAgents" in New Drugs for Asthma, Barnes, ed. IBC Technical ServicesLtd., 1989]. Research indicates that inhibition of this enzyme not onlyproduces airway smooth muscle relaxation, but also suppressesdegranulation of mast cells, basophils and neutrophils along withinhibiting the activation of monocytes and neutrophils. Moreover, thebeneficial effects of PDE IV inhibitors are markedly potentiated whenadenylate cyclase activity of target cells is elevated by appropriatehormones or autocoids, as would be the case in vivo. Thus PDE IVinhibitors would be effective in the asthmatic lung, where levels ofprostaglandin E₂ and prostacyclin (activators of adenylate cyclase) areelevated. Such compounds would offer a unique approach toward thepharmacotherapy of bronchial asthma and possess significant therapeuticadvantages over agents currently on the market.

The compounds of this invention also inhibit the production of TumorNecrosis Factor (TNF), a serum glycoprotein. Excessive or unregulatedTNF production has been implicated in mediating or exacerbating a numberof diseases including rheumatoid arthritis, rheumatoid spondylitis,osteoarthritis, gouty arthritis and other arthritic conditions; sepsis,septic shock, endotoxic shook, gram negative sepsis, toxic shooksyndrome, adult respiratory. distress syndrome, cerebral malaria,chronic pulmonary inflammatory disease, silicosis, pulmonarysarcoidosis, bone resorption diseases, reperfusion injury, graft vs.host reaction, allograft rejections, fever and myalgias due toinfection, such as influenza, cachexia secondary to infection ormalignancy, cachexia secondary to human acquired immune deficiencysyndrome (AIDS), AIDS, ARC (AIDS related complex), keloid formation,scar tissue formation, Crohn's disease, ulcerative colitis, or pyresis,in addition to a number of autoimmune diseases, such as multiplesclerosis, autoimmune diabetes and systemic lupus erythematosis.

AIDS results from the infection of T lymphocytes with HumanImmunodeficiency Virus (HIV). At least three types or strains of HIVhave been identified, i.e., HIV-1, HIV-2 and HIV-3. As a consequence ofHIV infection, T-cell-mediated immunity is impaired and infectedindividuals manifest severe opportunistic infections and/or unusualneoplasms. HIV entry into the T lymphocyte requires T lymphocyteactivation. Viruses such as HIV-1 or HIV-2 infect T lymphocytes after Tcell activation and such virus protein expression and/or replication ismediated or maintained by such T cell activation. Once an activated Tlymphocyte is infected with HIV, the T lymphocyte must continue to bemaintained in an activated state to permit HIV gene expression and/orHIV replication.

Cytokines, specifically TNF, are implicated in activated T-cell-mediatedHIV protein expression and/or virus replication by playing a role inmaintaining T lymphocyte activation. Therefore, interference withcytokine activity such as by inhibition of cytokine production, notablyTNF, in an HIV-infected individual aids in limiting the maintenance of Tcell activation, thereby reducing the progression of HIV infectivity topreviously uninfected cells which results in a slowing or elimination ofthe progression of immune dysfunction caused by HIV infection.Monocytes, macrophages, and related cells, such as kupffer and glialcells, have also been implicated in maintenance of the HIV infection.These cells, like T cells, are targets for vital replication and thelevel of viral replication is dependent upon the activation state of thecells. [See Rosenberg et al., The Immunopathogenesis of HIV Infection,Advances in Immunology, Vol. 57, 1989]. Monokines, such as TNF, havebeen shown to activate HIV replication in monocytes and/or macrophages[See Poli et al., Proc. Natl. Acad. Sci., 87:782-784, 1990], therefore,inhibition of monokine production or activity aids in limiting HIVprofession as stated above for T cells.

TNF has also been implicated in various roles with other viralinfections, such as the cytomegalovirus (CMV), influenza virus,adenovirus, and the herpes virus for similar reasons as those noted.

TNF is also associated with yeast and fungal infections. SpecificallyCandida albicans has been shown to induce TNF production in vitro inhuman monocytes and natural killer cells. [See Riipi et al., Infectionand Immunity, 58(9):2750-54, 1990; and Jafari et al., Journal ofInfectious Diseases, 164:389-95, 1991. See also Wasan et al.,Antimicrobial Agents and Chemotherapy, 35, (10):2046-48, 1991; and Lukeet al., Journal of Infectious Diseases, 162:211-214,1990].

The ability to control the adverse effects of TNF is furthered by theuse of the compounds which inhibit TNF in mammals who are in need ofsuch use. There remains a need for compounds which are useful intreating TNF-mediated disease states which are exacerbated or caused bythe excessive and/or unregulated production of TNF.

SUMMARY OF THE INVENTION

This invention relates to the novel compounds of Formula (I), as shownbelow, useful in the mediation or inhibition of the enzymatic activity(or catalytic activity) of phosphodiesterase IV (PDE IV). The novelcompounds of Formula (I) also have Tumor Necrosis Factor (TNF)inhibitory activity.

This invention also relates to the pharmaceutical compositionscomprising a compound of Formula (I) and a pharmaceutically acceptablecarrier or diluent.

The invention also relates to a method of mediation or inhibition of theenzymatic activity (or catalytic activity) of PDE IV in mammals,including humans, which comprises administering to a mammal in needthereof an effective amount of a compound of Formula (I), as shownbelow.

The invention further provides a method for the treatment of allergicand inflammatory disease which comprises administering to a mammal,including humans, in need thereof, an effective amount of a compound ofFormula (I).

The invention also provides a method for the treatment of asthma whichcomprises administering to a mammal, including humans, in need thereof,an effective amount of a compound of Formula (I).

This invention also relates to a method of inhibiting TNF production ina mammal, including humans, which method comprises administering to amammal in need of such treatment, an effective TNF inhibiting amount ofa compound of Formula (I). This method may be used for the prophylactictreatment or prevention of certain TNF mediated disease states amenablethereto.

This invention also relates to a method of treating a human afflictedwith a human immunodeficiency virus (HIV), which comprises administeringto such human an effective TNF inhibiting amount of a compound ofFormula (I).

The compounds of Formula (I) are also useful in the treatment ofadditional viral infections, where such viruses are sensitive toupregulation by TNF or will elicit TNF production in vivo.

The compounds of Formula (I) are also useful in the treatment of yeastand fungal infections, where such yeast and fungi are sensitive toupregulation by TNF or will elicit TNF production in vivo.

The compounds of this invention are represented by Formula (I): ##STR2##wherein: R₁ is --(CR₄ R₅)_(n) C(O)O(CR₄ R₅)_(m) R₆, --(CR₄ R₅)_(n)C(O)NR₄ (CR₄ R₅)_(m) R₆, --(CR₄ R₅)_(n) O(CR₄ R₅)_(m) R₆, or --(CR₄R₅)_(r) R₆ wherein the alkyl moieties may be optionally substituted withone or more halogens;

m is 0 to 2;

n is 1 to 4;

r is 1 to 6;

R₄ and R₅ are independently selected from hydrogen or C₁₋₂ alkyl;

R₆ is hydrogen, methyl, hydroxyl, aryl, halo substituted aryl,aryloxyC₁₋₃ alkyl, halo substituted aryloxyC₁₋₃ alkyl, indenyl, indenyl,C₇₋₁₁ polycycloalkyl, tetrahydrofuranyl, furanyl, tetrahydropyranyl,pyranyl, tetrahydrothienyl, thienyl, tetrahydrothiopyranyl, thiopyranyl,C₃₋₆ cycloalkyl, or a C₄₋₆ cycloalkyl containing one or two unsaturatedbonds, wherein the cycloalkyl and heterocyclic moieties may beoptionally substituted by 1 to 3 methyl groups or one ethyl group;

provided that:

a) when R₆ is hydroxyl, then m is 2; or

b) when R₆ is hydroxyl, then r is 2 to 6; or

c) when R₆ is 2-tetrahydropyranyl, 2-tetrahydrothiopyranyl,2-tetrahydrofuranyl, or 2-tetrahydrothienyl, then m is 1 or 2; or

d) when R₆ is 2-tetrahydropyranyl, 2-tetrahydrothiopyranyl,2-tetrahydrofuranyl, or 2-tetrahydrothienyl, then r is 1 to 6;

e) when n is 1 and m is 0, then R₆ is other than H in --(CR₄ R₅) _(n)O(CR₄ R₅)_(m) R₆ ;

X is YR₂, halogen, nitro, NR₄ R₅, or formyl amine;

Y is O or S(O)_(m') ;

m' is 0, 1, or 2;

X2 is O or NR₈ ;

X₃ is hydrogen or X;

R₂ is independently selected from --CH₃ or --CH₂ CH₃ optionallysubstituted by 1 or more halogens;

s is 0 to 4;

R₃ is hydrogen, halogen, C₁₋₄ alkyl, CH₂ NHC(O)C(O)NH₂, halo-substitutedC₁₋₄ alkyl, --CH═CR_(8') R_(8'), cyclopropyl optionally substituted byR_(8'), CN, OR₈, CH₂ OR₈, NR₈ R₁₀, CH₂ NR₈ R₁₀, C(Z')H, C(O)OR₈, C(O)NR₈R₁₀, or C.tbd.CR_(8';)

Z' is O, NR₉, NOR₈, NCN, C(--CN)₂, CR₈ CN, CR₈ NO₂, CR₈ C(O)OR₈, CR₈C(O)NR₈ R₈, C(--CN)NO₂,C(--CN)C(O)OR₉, or C(--CN)C(O)NR₈ R₈ ;

Z is CR₈ R₈ OR₁₄, CR₈ R₈ OR15, CR₈ R₈ SR₁₄, CR₈ R₈ SR₁₅, CR₈ R₈S(O)_(m') R₇, CR₈ R₈ NR₁₀ R₁₄, CR₈ R₈ NR₁₀ S(O)₂ NR₁₀ R₁₄, CR₈ R₈ NR₁₀S(O)₂ R₇, CR₈ R₈ NR₁₀ C(Y')R₁₄, CR₈ R₈ NR₁₀ C(O)OR₇, CR₈ R₈ NR₁₀C(Y')NR₁₀ R₁₄, CR₈ R₈ NR₁₀ C(NCN)NR₁₀ R₁₄, CR₈ R₈ NR₁₀ C(CR₄ NO₂)NR₁₀R₁₄, CR₈ R₈ NR₁₀ C(NCN)SR₉, CR₈ R₈ NR₁₀ C(CR₄ NO₂)SR₉, CR₈ R₈ C(O)OR14,CR₈ R₈ C(Y')NR₁₀ R₁₄, CR₈ R₈ C(NR₁₀)NR₁₀ R₁₄, CR₈ R₈ CN, CR₈ R₈(tetrazolyl), CR₈ R₈ (imidazolyl), CR₈ R₈ (imidazolidinyl), CR₈ R₈(pyrazolyl), CR₈ R₈ (thiazolyl), CR₈ R₈ (thiazolidinyl), CR₈ R₈(oxazolyl), CR₈ R₈ (oxazolidinyl), CR₈ R₈ (triazolyl), CR₈ R₈(isoxazolyl), CR₈ R₈ (oxadiazolyl), CR₈ R₈ (thiadiazolyl), CR₈ R₈(morpholinyl), CR₈ R₈ (piperidinyl), CR₈ R₈ (piperazinyl), CR₈ R₈(pyrrolyl), CR₈ R₈ C(NOR₈)R₁₄, CR₈ R₈ C(NOR ₁₄)R8, CR₈ R₈ NR₁₀C(NR₁₀)SR₉, CR₈ R₈ NR₁₀ C (NR₁₀)NR₁₀ R₁₄, CR₈ R₈ NR₁₀ C(O)C(O)NR₁₀ R₁₄,or CR₈ R₈ NR₁₀ C(O)C(O)OR₁₄ ;

X₅ is H, R₉, OR₈, CN, C(O)R₈, C(O)OR₈, C(O)NR₈ R₈, or NR₈ R₈ ; or Z andX₅ together is --CR₈ R₈ O--;

Y' is O or S;

R₇ is --(CR₄ R₅)_(q) R₁₂ or C₁₋₆ alkyl wherein the R₁₂ or C₁₋₆ alkylgroup is optionally substituted one or more times by C₁₋₂ alkyloptionally substituted by one to three fluorines, --F, --Br, --Cl,--NO₂, --NR₁₀ R₁₁, --C(O)R₈, --C(O)OR₈, --OR₈, --CN, --C(O)NR₁₀ R₁₁,--OC(O)NR₁₀ R₁₁, --OC(O)R₈, --NR₁₀ C(O)NR₁₀ R₁₁, --NR₁₀ C(O)R₁₁, --NR₁₀C(O)OR₉, --NR₁₀ C(O)R₁₃, --C(NR₁₀)NR₁₀ R₁₁, --C(NCN)NR₁₀ R₁₁,--C(NCN)SR₉, --NR₁₀ C(NCN)SR₉, --NR₁₀ C(NCN)NR₁₀ R₁₁, --NR₁₀ S(O)₂ R₉,--S(O)_(m') R₉, --NR₁₀ C(O)C(O)NR₁₀ R₁₁, --NR₁₀ C(O)C(O)R₁₀, thiazolyl,imidazolyl, oxazolyl, pyrazolyl, triazolyl, or tetrazolyl;

q is 0, 1, or 2;

R₁₂ is C₃₋₇ cycloalkyl, (2-, 3-or 4-pyridyl), pyrimidyl, pyrazolyl,(1-or 2-imidazolyl) thiazolyl, triazolyl, pyrrolyl, piperazinyl,piperidinyl, morpholinyl, furanyl, (2-or 3-thienyl), (4- or5-thiazolyl), quinolinyl, naphthyl, or phenyl;

R₈ is independently selected from hydrogen or R₉ ;

R_(8'), is R₈ or fluorine;

R₉ is C₁₋₄ alkyl optionally substituted by one to three fluorines;

R₁₀ is OR₈ or R₁₁ ;

R₁₁ is hydrogen, or C₁₋₄ alkyl optionally substituted by one to threefluorines; or when R₁₀ and R₁₁ are as NR10R₁₁ they may together with thenitrogen form a 5 to 7 membered ting optionally containing at least oneadditional heteroatom selected from O, N, or S;

R₁₃ is oxazolidinyl, oxazolyl, thiazolyl, pyrazolyl, triazolyl,tetrazolyl, imidazolyl, imidazolidinyl, thiazolidinyl, isoxazolyl,oxadiazolyl, or thiadiazolyl, and each of these heterocyclic rings isconnected through a carbon atom and each may be unsubstituted orsubstituted by one or two C₁₋₂ alkyl groups;

R₁₄ is hydrogen or R₇ ; or when R₁₀ and R₁₄ are as NR₁₀ R₁₄ they maytogether with the nitrogen form a 5 to 7 membered ring optionallycontaining one or more additional heteroatoms selected from O, N, or S;

R₁₅ is C(O)R₁₄, C(O)NR₈ R₁₄, S(O)₂ NR₈ R₁₄, S(O)₂ R₇ ;

provided that:

f) when R₁₂ is N-pyrazolyl, N-imidazolyl, N-triazolyl, N-pyrrolyl,N-piperazinyl, N-piperidinyl, or N-morpholinyl, then q is not 1;

g) when X₂ R₁ is OCF₂ H or OCF₃, X is F, OCF₂ H or OCF₃, X₃ is H, s iszero, X₅ is H, Z is CH₂ OR₁₄, and R₁₄ is C₁₋₇ unsubstituted alkyl, thenR₃ is other than H;

or a pharmaceutically acceptable salt thereof.

DETAILED DESCRIPTION OF THE INVENTION

This invention relates to the novel compounds of Formula (I), and topharmaceutical compositions comprising a compound of Formula (I) and apharmaceutically acceptable carrier or diluent. This invention alsorelates to a method of mediating or inhibiting the enzymatic activity(or catalytic activity) of PDE IV in a mammal in need thereof and toinhibiting the production of TNF in a mammal in need thereof, whichcomprises administering to said mammal an effective amount of a compoundof Formula (I).

Phosphodiesterase IV inhibitors are useful in the treatment of a varietyof allergic and inflammatory diseases including: asthma, chronicbronchitis, atopic dermatitis, urticaria, allergic rhinitis, allergicconjunctivitis, vernal conjunctivitis, eosinophilic granuloma,psoriasis, rheumatoid arthritis, septic shock, ulcerative colitis,Crohn's disease, reperfusion injury of the myocardium and brain, chronicglomerulonephritis, endotoxic shock and adult respiratory distresssyndrome. In addition, PDE IV inhibitors are useful in the treatment ofdiabetes insipidus, [Kidney Int., 37:362, 1990; Kidney Int., 35:494,1989] and central nervous system disorders such as depression andmulti-infarct dementia.

The compounds of Formula (I) are also useful in the treatment of viralinfections, where such viruses are sensitive to upregulation by TNF orwill elicit TNF production in vivo. The viruses contemplated fortreatment herein are those that produce TNF as a result of infection, orthose which are sensitive to inhibition, such as by decreasedreplication, directly or indirectly, by the TNF inhibitors of Formula (1). Such viruses include, but are not limited to HIV-1, HIV-2 and HIV-3,cytomegalovirus (CMV), influenza, adenovirus and the Herpes group ofviruses, such as, but not limited to, Herpes zoster and Herpes simplex.

This invention more specifically relates to a method of treating amammal, afflicted with a human immunodeficiency virus (HIV), whichcomprises administering to such mammal an effective TNF inhibitingamount of a compound of Formula (I).

The compounds of Formula (I) may also be used in association with theveterinary treatment of animals, other than in humans, in need ofinhibition of TNF production. TNF mediated diseases for treatment,therapeutically or prophylactically, in animals include disease statessuch as those noted above, but in particular viral infections. Examplesof such viruses include, but are not limited to feline immunodeficiencyvirus (FIV) or other retroviral infection such as equine infectiousanemia virus, caprine arthritis virus, visna virus, maedi virus andother lentiviruses.

The compounds of Formula (I) are also useful in the treatment of yeastand fungal infections, where such yeast and fungi are sensitive toupregulation by TNF or will elicit TNF production in vivo. A preferreddisease state for treatment is fungal meningitis. Additionally, thecompounds of Formula (I) may be administered in conjunction with otherdrugs of choice for systemic yeast and fungal infections. Drugs ofchoice for fungal infections, include but are not limited to the classof compounds called the polymixins, such as Polymycin B, the class ofcompounds called the imidazoles, such as clotrimazole, econazole,miconazole, and ketoconazole; the class of compounds called thetriazoles, such as fluconazole, and itranazole, and the class ofcompound called the Amphotericins, in particular Amphotericin B andliposomal Amphotericin B.

The co-administration of the anti-fungal agent with a compound ofFormula (I) may be in any preferred composition for that compound suchas is well known to those skilled in the art, for instance the variousAmphotericin B formulations. Co-administration of an antifungal agentwith a compound of Formula (I) may mean simultaneous administration orin practice, separate administration of the agents to the mammal but ina consecutive manner. In particular, the compounds of Formula (I) may beco-administered with a formulation of Amphotericin B, notably forsystemic fungal infections. The preferred organism for treatment is theCandida organism. The compounds of Formula (I) may be co-administered ina similar manner with anti-viral or anti-bacterial agents.

The compounds of Formula (I) may also be used for inhibiting and/orreducing the toxicity of an anti-fungal, anti-bacterial or anti-viralagent by administering an effective amount of a compound of Formula (I)to a mammal in need of such treatment. Preferably, a compound of Formula(I) is administered for inhibiting or reducing the toxicity of theAmphotericin class of compounds, in particular Amphotericin B.

Preferred compounds are as follows:

When R₁ for the compounds of Formula (I) is an alkyl substituted by 1 ormore halogens, the halogens are preferably fluorine and chlorine, morepreferably a C₁₋₄ alkyl substituted by 1 or more fluorines. Thepreferred halo-substituted alkyl chain length is one or two carbons, andmost preferred are the moieties --CF₃, --CH₂ F, --CHF₂, --CF₂ CHF₂,--CH₂ CF₃, and --CH₂ CHF₂. Preferred R₁ substitutents for the compoundsof Formula (I) are CH₂ -cyclopropyl, CH₂ --C₅₋₆ cycloalkyl, C₄₋₆cycloalkyl, C₇₋₁₁ polycycloalkyl, (3- or 4-cyclopenteny), phenyl,tetrahydrofuran-3-yl, benzyl or C₁₋₂ alkyl optionally substituted by 1or more fluorines, --(CH₂)₁₋₃ C(O)O(CH₂)₀₋₂ CH₃, --(CH₂)₁₋₃ (CH₂)₀₋₂CH₃, and --(CH₂)₂₋₄ OH.

When the R₁ term contains the moiety (CR₄ R₅), the R₄ and R₅ terms areindependently hydrogen or alkyl. This allows for branching of theindividual methylene units as (CR₄ R₅)_(n) or (CR₄ R₅)_(m) ; eachrepeating methylene unit is independent of the other, e.g., (CR₄ R₅)_(n)wherein n is 2 can be --CH₂ CH(--CH₃)--, for instance. The individualhydrogen atoms of the repeating methylene unit or the branchinghydrocarbon can optionally be substituted by fluorine independent ofeach other to yield, for instance, the preferred R₁ substitutions, asnoted above.

When R₁ is a C₇₋₁₁ polycycloalkyl, examples are bicyclo[2.2.1]-heptyl,bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl, tricyclo[5.2.1.0²,6 ]decyl,etc. additional examples of which are described in Saccamano et al., WO87/06576, published 5 November 1987, whose disclosure is incorporatedherein by reference in its entirety.

Z is preferably CR₈ R₈ OR₁₄, CR₈ R₈ OR₁₅, CR₈ R₈ SR₁₄, CR₈ R₈ SR₁₅, CR₈R₈ S(O)_(m') R₇, CR₈ R₈ NR₁₀ R₁₄, CR₈ R₈ NS(O)₂ NR₁₀ R₁₄, CR₈ R₈ NS(O)₂R₇, CR₈ R₈ NR₁₀ C(O)R₁₄, CR₈ R₈ NR₁₀ C(O)OR₇, CR₈ R₈ NR₁₀ C(O)NR₁₀ R₁₄,CR₈ R₈ NR₁₀ C(NCN)NR₁₀ R₁₄, CR₈ R₈ NR₁₀ C (CR₄ NO₂)NR₁₀ R₁₄, CR₈ R₈ NR₁₀C(NCN)SR₉, CR₈ R₈ NR₁₀ C(CR₄ NO₂)SR₉, CR₈ R₈ C(O)OR₁₄, CR₈ R₈ C(O)NR₁₀R₁₄, CR₈ R₈ C(NR₁₀)NR₁₀ R₁₄, CR₈ R₈ CN, CR₈ R₈ C(NOR₈)R₁₄, CR₈ R₈C(NOR₁₄)R₈, CR₈ R₈ NR₁₀ C(NR₁₀)SR₉, CR₈ R₈ NR₁₀ C(NR₁₀)NR₁₀ R₁₄, CR₈ R₈NR₁₀ C(O)C(O)NR₁₀ R₁₄, or CR₈ R₈ NR₁₀ C(O)C(O)OR₁₄ ;most preferred arethose compounds wherein the R₈ group of Z is H and the R₁₄ group of Z isR₄.

Preferred X₅ groups are H, OH, OCH₃, CN, C(O)R₈, C(O)OH, C(O)OCH₃,C(O)NH₂, CON(CH₃)₂, NH₂, or N(CH₃)₂. The most preferred groups are H,OH, CN, C(O)OH, C(O)NH₂ or NH₂.

The preferred group wherein Z and X₅ together is --CR₈ R₈ CO--is --CH₂CO--.

Preferred X groups for Formula (I) are those wherein X is YR₂ and Y isoxygen. The preferred X₂ group for Formula (I) is that wherein X₂ isoxygen. The preferred X₃ group for Formula (I) is that wherein X₃ ishydrogen. Preferred R₂ groups, where applicable, is a C₁₋₂ alkyloptionally substituted by 1 or more halogens. The halogen atoms arepreferably fluorine and chlorine, more preferably fluorine. Morepreferred R₂ groups are those wherein R₂ is methyl, or thefluoro-substituted alkyls, specifically a C₁₋₂ alkyl, such as a --CF₃,--CHF₂, or --CH₂ CHF₂ moiety. Most preferred are the --CHF₂ and --CH₃moieties.

Preferred R₃ moieties are C(O)NH₂, C.tbd.CR₈, CH₂ NHC(O)C(O)NH₂, CN,C(Z')H, CH₂ OH, CH₂ F, CF₂ H, and CF₃. More preferred are C.tbd.CH andCN. Z' is preferably O or NOR₈.

Preferred R₇ moieties include optionally substituted --(CH₂)₁₋₂(cyclopropyl), --(CH₂)₀₋₂ (cyclobutyl), --(CH₂)₀₋₂ (cyclopentyl),--(CH₂)₀₋₂ (cyclohexyl),--(CH₂)₀₋₂ (2-, 3- or 4-pyridyl), (CH₂)₁₋₂(2-imidazolyl), (CH₂)₂ (4-morpholinyl), (CH₂)₂ (4-piperazinyl), (CH₂)₁₋₂(2-thienyl), (CH₂)₁₋₂ (4-thiazolyl), and (CH₂)₀₋₂ phenyl;

Preferred rings when R₁₀ and R₁₁ in the moiety --NR₁₀ R₁₁ together withthe nitrogen to which they are attached form a 5 to 7 membered ringoptionally containing at least one additional heteroatom selected fromO, N, or S include, but are not limited to 1-imidazolyl,2-(R₈)-1-imidazolyl, 1-pyrazolyl, 3-(R₈)-1-pyrazolyl, 1-triazolyl,2-triazolyl, 5-(R₈)-1-triazolyl, 5-(R₈)-2-triazolyl,5-(R₈)-1-tetrazolyl, 5-(R₈)-2-terazolyl, 1-tetrazolyl, 2-tetrazloyl,morpholinyl, piperazinyl, 4-(R₈)-1-piperazinyl, or pyrrolyl ring.

Preferred rings when R₁₀ and R₁₄ in the moiety --NR₁₀ R₁₄ together withthe nitrogen to which they are attached may form a 5 to 7 membered tingoptionally containing at least one additional heteroatom selected fromO, N, or S include, but are not limited to 1-imidazolyl, 1-pyrazolyl,1-triazolyl, 2-triazolyl, 1-tetrazolyl, 2-tetrazolyl, morpholinyl,piperazinyl, and pyrrolyl. The respective rings may be additionallysubstituted, where applicable, on an available nitrogen or carbon by themoiety R₇ as described herein for Formula (I). Illustrations of suchcarbon substitutions includes, but are not limited to,2-(R₇)-1-imidazolyl, 4-(R₇)-1-imidazolyl, 5-(R₇)-1-imidazolyl,3-(R7)-1-pyrazolyl 4-(R₇)-1-pyrazolyl, 5-(R₇)-1-pyrazolyl,4-(R₇)-2-triazolyl, 5-(R₇)-2-triazolyl, 4-(R₇)-1-triazolyl,5-(R₇)-1-triazolyl, 5-(R₇)-1-tetrazolyl, and 5-(R₇)-2-tetrazolylApplicable nitrogen substitution by R7 includes, but is not limited to,1-(R₇)-2-tetrazolyl, 2-(R₇)-1-tetrazolyl, 4-(R₇)-1-piperazinyl. Whereapplicable, the ring may be substituted one or more times by R7.

Preferred groups for NR₁₀ R₁₄ which contain a heterocyclic ting are5-(R₁₄)-1-tetrazolyl, 2-(R₁₄)-1-imidazolyl, 5-(R₁₄)-2-tetrazolyl, or4-(R₁₄)-1-piperazinyl.

Preferred rings for R₁₃ include (2-, 4- or 5-imidazolyl), (3-, 4- or5-pyrazolyl), (4- or 5-triazolyl[1,2,3]), (3- or 5-triazolyl[1,2,4]),(5-tetrazolyl), (2-, 4- or 5-isoxazolyl),(3-,4- or5-isoxazolyl), (3-or5-oxadiazolyl[1,2,4]), (2-oxadiazolyl[1,3,4]), (2-thiadiazolyl [1,3,4]),(2-, 4-, or 5-thiazolyl), (2-, 4-, or 5-oxazolidinyl), (2-, 4-, or5-thiazolidinyl), or (2, 4-, or 5-imidazolidinyl).

When the R₇ group is optionally substituted by a heterocyclic ting suchas imidazolyl, pyrazolyl, triazolyl, tetrazolyl, or thiazolyl, theheterocyclic ring itself may be optionally substituted by R₈ either onan available nitrogen or carbon atom, such as 1-(R₈)-2-imidazolyl,1-(R₈)-4-imidazolyl, 1-(R₈)-5-imidazolyl, 1-(R₈)-3-pyrazolyl,1-(R₈)-4-pyrazolyl, 1-(R₈)-5-pyrazolyl, 1-(R₈)-4-triazolyl, or1-(R₈)-5-triazolyl. Where applicable, the ring may be substituted one ormore times by R₈.

Preferred are those compounds of Formula (I) wherein R₁ is -CH₂-cyclopropyl, --CH₂ --C₅₋₆ cycloalkyl, --C₄₋₆ cycloalkyl,tetrahydrofuran-3-yl, (3- or 4-cyclopentenyl), benzyl or -C₁₋₂ alkyloptionally substituted by 1 or more fluorines, and --(CH₂)₂₋₄ OH; R₂ ismethyl or fluoro-substituted alkyl, R₃ is CN or C.tbd.CR₈ ; and X isYR₂.

Most preferred are those compounds wherein R₁ is --CH₂ -cyclopropyl,cyclopentyl, methyl or CF₂ H; R₃ is CN or C.tbd.CH; X is YR₂ ; Y isoxygen; X₂ is oxygen; X₃ is hydrogen; and R₂ is CF₂ H or methyl.

A preferred subgenus of the compounds of Formula (I) is the compounds ofFormula (Ia) ##STR3## wherein: R₁ is CH₂ -cyclopropyl, CH₂ --C₅₋₆cycloalkyl, C₄₋₆ cycloalkyl, C₇₋₁₁ polycycloalkyl, (3- or4-cyclopentenyl), phenyl, tetrahydrofuran-3-yl, benzyl or C ₁₋₂ alkyloptionally substituted by 1 or more fluorines, --(CH₂)₁₋₃ C(O)O(CH₂)₀₋₂CH3, --(CH₂)₁₋₃ O(CH₂)₀₋₂ CH₃, and --(CH₂)₂₋₄ OH;

X is YR₂, halogen, nitro, NR₄ R₅, or formyl amine;

Y is O or S(O)_(m';)

m' is 0, 1, or 2;

R₂ is--CH₃ or--CH₂ CH₃ optionally substituted by 1 or more halogens;

R₃ is hydrogen, C₁₋₄ alkyl, CH₂ NHC(O)C(O)NH₂, halo-substituted C₁₋₄alkyl, CN, CH₂ OR₈, C(Z')H, C(O)OR₈, C(O)NR₈ R₁₀, or C.tbd.CR₈ ;

Z' is O or NOR₈ ;

Z is CR₈ R₈ OR₁₄, CR₈ R₈ OR₁₅, CR₈ R₈ SR₁₄, CR₈ R₈ SR₁₅, CR₈ R₈S(O)_(m'R) ₇, CR₈ R₈ NR₁₀ R₁₄, CR₈ R₈ NS(O)₂ NR₁₀ R₁₄, CR₈ R₈ NS(O)₂ R₇,CR₈ R₈ NR₁₀ C(Y')R₁₄, CR₈ R₈ NR₁₀ C(O)OR₇, CR₈ R₈ NR₁₀ C(Y')NR₁₀ R₁₄,CR₈ R₈ NR₁₀ C(NCN)NR₁₀ R₁₄, CR₈ R₈ NR₁₀ C(CR₄ NO₂)NR₁₀ R₁₄, CR₈ R₈ NR₁₀C(NCN)SR₉, CR₈ R₈ NR₁₀ C(CR₄ NO₂)SR₉, CR₈ R₈ C(Y')OR₁₄, CR₈ R₈ C(Y')NR₁₀R₁₄, CR₈ R₈ C(NR₁₀)NR₁₀ R₁₄, CR₈ R₈ CN, CR₈ R₈ C (NOR₈)R₁₄, CR₈ R₈C(NOR₁₄)R₈, CR₈ R₈ NR₁₀ C(NR₁₀)SR₉, CR₈ R₈ NR₁₀ C(NR₁₀)NR₁₀ R₁₄, CR₈ R₈NR₁₀ C(O)C(O)NR₁₀ R₁₄, or CR₈ R₈ NR₁₀ C(O)C(O)OR₁₄ ;

X₅ is H, OR₈, CN, C(O)OR₈ or NR₈ R₈ ; or Z and X₅ together is --CR₈ R₈CO--;

Y' is O or S;

R₇ is --(CR₄ R₅)_(q) R₁₂ or C₁₋₆ alkyl wherein the R₁₂ or C₁₋₆ alkylgroup is optionally substituted one or more times by methyl or ethylsubstituted by 1-3 fluorines, --F, --Br, --Cl, --NO₂, --NR₁₀ R₁₁,--C(O)R₈, --C(O)OR₈, --OR₈, ---CN, --C(O)NR₁₀ R₁₁, 13 OC(O)NR₁₀ R₁₁,--OC(O)R₈, --NR₁₀ C(O)NR₁₀ R₁₁, --NR₁₀ C(O)R₁₁, --NR₁₀ C(O)OR₉, --NR₁₀C(O)R₁₃, --C(NR₁₀)NR₁₀ R₁₁, --C(NCN)NR₁₀ R₁₁, --C(NCN)SR₉, --NR₁₀C(NCN)SR₉, --NR₁₀ C(NCN)NR₁₀ R₁₁, --NR₁₀ S(O)₂ R₉, --S(O)_(m') R₉,--NR₁₀ C(O)C(O)NR₁₀ R₁₁, --NR₁₀ C(O)C(O)R₁₀, thiazolyl, imidazolyl,oxazolyl, pyrazolyl, triazolyl, or tetrazolyl;

q is 0, 1, or 2;

R₁₂ is C₃ -C₇ cycloalkyl, (2-, 3- or 4-pyridyl), (1- or 2-imidazolyl),piperazinyl, morpholinyl, (2- or 3-thienyl), (4- or 5-thiazolyl), orphenyl;

R₈ is independently selected from hydrogen or R₉ ;

R₉ is C₁₋₄ alkyl optionally substituted by one to three fluorines;

R₁₀ is OR₈ or R₁₁ ;

R₁₁ is hydrogen or C₁₋₄ alkyl optionally substituted by one to threefluorines; or when R₁₀ and R₁₁ are as NR₁₀ R₁₁ they may together withthe nitrogen form a 5 to 7 membered ring optionally containing at leastone additional heteroatom selected from O, N, or S;

R₁₃ is oxazolidinyl, oxazolyl, thiazolyl, pyrazolyl, triazolyl,tetrazolyl, imidazolyl, imidazolidinyl, thiazolidinyl, isoxazolyl,oxadiazolyl, or thiadiazolyl, and each of these heterocyclic rings isconnected through a carbon atom and each may be unsubstituted orsubstituted by one or two C₁₋₂ alkyl groups;

R₁₄ is hydrogen or R₇ ; or when R₁₀ and R₁₄ are as NR₁₀ R₁₄ they maytogether with the nitrogen form a 5 to 7 membered ring optionallycontaining one or more additional heteroatoms selected from O, N, or S;

R₁₅ is C(O)R₁₄, C(O)NR₈ R₁₄, S(O)₂ NR₈ R₁₄, S(O)₂ R₇ ;

provided that:

a) when R₁₂ is N-imidazolyl, N-triazolyl, N-pyrrolyl, N-piperazinyl, orN-morpholinyl, then q is not 1;

b) when R₁ is CF₂ H or CF₃, X is F, OCF₂ H or OCF₃, X₅ is H, Z is CH₂OR₁₄, and R₁₄ is C₁₋₇ unsubstituted alkyl, then R₃ is other than H;

or the pharmaceutically acceptable salts thereof.

Preferred compounds of Formula (I) are:

methyl2-[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-1-yl]acetate;

cis-[4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)cyclohexan-1-yl]methanol;

cis-[4-cyano-4-( 3-cyclopropylmethoxy-4-methoxyphenyl )cyclohexan-1-yl]methylamine;

cis-[4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)cyclohexan-1,1-diyl]oxirane;

cis-[4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)-1-hydroxycyclohexan-1-yl]methanol;

trans-[4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)cyclohexan-1,1-diyl]oxirane;and

trans-[4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)-1-hydroxycyclohexan-1-yl]methanol.

Some of the compounds of Formula (I) may exist in both racemic andoptically active forms; some may also exist in distinct diastereomericforms. All of these compounds are considered to be within the scope ofthe present invention. Therefore another aspect of the present inventionis the administration of either a racemate, a single enantiomeric form,a single diastereomeric form, or mixtures thereof.

DEFINITIONS

The terms "C₁₋₃ alkyl", "C₁₋₄ alkyl", "C₁₋₆ alkyl" or "alkyl" includeboth straight or branched chain radicals of 1 to 10, unless the chainlength is limited thereto, including, but not limited to methyl, ethyl,n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, and thelike. "Alkenyl" includes both straight or branched chain radicals of 1to 6 carbon lengths, unless the chain length is limited thereto,including but not limited to vinyl, 1-propenyl, 2-propenyl, 2-propynyl,or 3-methyl-2-propenyl. "Cycloalkyl" or "cycloalkyl alkyl" includesradicals of 3-7 carbon atoms, such as cyclopropyl, cyclopropylmethyl,cyclopentyl, or cyclohexyl. "Aryl" or "aralkyl", unless specifiedotherwise, means an aromatic ring or ring system of 6-10 carbon atoms,such as phenyl, benzyl, phenethyl, or naphthyl. Preferably the aryl ismonocyclic, i.e, phenyl. The alkyl chain is meant to include bothstraight or branched chain radicals of 1 to 4 carbon atoms. "Heteroaryl"means an aromatic ring system containing one or more heteroatoms, suchas imidazolyl, triazolyl, oxazolyl, pyridyl, pyrimidyl, pyrazolyl,pyrrolyl, furanyl, or thienyl. "Halo" means chloro, fluoro, bromo, oriodo.

By the phrase "inhibiting the production of IL-1" or "inhibiting theproduction of TNF" means:

a) a decrease of excessive in vivo IL-1 or TNF levels, respectively, ina human to normal levels or below normal levels by inhibition of the invivo release of IL-1 by all cells, including but not limited tomonocytes or macrophages;

b) a down regulation, at the translational or transcriptional level, ofexcessive in vivo IL-1 or TNF levels, respectively, in a human to normallevels or below normal levels; or

c) a down regulation, by inhibition of the direct synthesis of IL-1 orTNF levels as a postranslational event.

By the term "TNF mediated disease or disease states" is meant any andall disease states in which TNF plays a role, either by production ofTNF itself, or by TNF causing another cytokine to be released, such asbut not limited to IL-1 or IL-6. A disease state in which IL-1, forinstance is a major component, and whose production or action, isexacerbated or secreted in response to TNF, would therefore beconsidered a disease state mediated by TNF. As TNF-β (also known aslymphotoxin) has close structural homology with TNF-α (also known ascachectin), and since each induces similar biologic responses and bindsto the same cellular receptor, both TNF-α and TNF-β are inhibited by thecompounds of the present invention and thus are herein referred tocollectively as "TNF" unless specifically delineated otherwise.Preferably TNF-60 is inhibited.

"Cytokine" means any secreted polypeptide that affects the functions ofcells, and is a molecule which modulates interactions between cells inimmune, inflammatory, or hematopoietic responses. A cytokine includes,but is not limited to, monokines and lymphokines regardless of whichcells produce them. For instance, a monokine is generally referred to asbeing produced and secreted by a mononuclear cell, such as a macrophageand/or monocyte, but many other cells produce monokines, such as naturalkiller cells, fibroblasts, basophils, neutrophils, endothelial cells,brain astrocytes, bone marrow stromal cells, epidermal keratinocytes,and B-lymphocytes. Lymphokines are generally referred to as beingproduced by lymphocyte cells. Examples of cytokines for the presentinvention include, but are not limited to, Interleukin-1 (IL-1 ),Interleukin-6 (IL-6), Interleukin-8 (IL-8), Tumor Necrosis Factor-alpha(TNF-α) and Tumor Necrosis Factor-beta (TNF-β).

The cytokine inhibited by the present invention for use in the treatmentof a HIV-infected human must be a cytokine which is implicated in (a)the initiation and/or maintenance of T cell activation and/or activatedT cell-mediated HIV gene expression and/or replication, and/or (b) anycytokine-mediated disease associated problem such as cachexia or muscledegeneration. Preferrably, his cytokine is TNF-a.

The cytokine inhibited by the present invention for use in the treatmentof a HIV-infected human must be a cytokine which is implicated in (a)the initiation and/or maintenance of T cell activation and/or activatedT cell-mediated HIV gene expression and/or replication, and/or (b) anycytokine-mediated disease associated problem such as cachexia or muscledegeneration. Preferrably, his cytokine is TNF-α.

All of the compounds of Formula (I) are useful in the method ofinhibiting the production of TNF, preferably by macrophages, monocytesor macrophages and monocytes, in a mammal, including humans, in needthereof. All of the compounds of Formula (I) are useful in the method ofinhibiting or mediating the enzymatic or catalytic activity of PDE IVand in treatment of disease states mediated thereby.

METHODS OF PREPARATION

Preparing compounds of Formula (I) can be accomplished by one of skillin the art according to the procedures outlined in the Examples, infra.The preparation of any remaining compounds of Formula (I) not describedtherein may be prepared by the analogous processes disclosed hereinwhich comprise:

a) for compounds of Formula (I) wherein R₃ is other than C(═Z')H andwherein Z is CH₂ COOCH₃, reacting a compound of Formula (2) ##STR4##where R₁ represents R₁ as defined in relation to Formula (I) or a groupconvertable to R₁ and X and X₃ represent X and X₃ as defined in relationto Formula (I) or a group convertable to X or X₃ and R₃ represents R₃ asdefined in relation to Formula (I) or a group convertable to R₃, with astabilized acetate anion, such as sodium trimethylphosphonoacetate orlithium ethyl (trimethylsilyl)acetate, in a suitable non-reactingsolvent, such as 1,2-dimethoxyethane or tetrahydrofuran, followed byreduction of the resulting ethylidene intermediate with, e.g., hydrogenand a suitable catalyst, to provide compounds of Formula (I) wherein R₃is other than C(═Z')H and wherein Z is CH₂ COOCH₃ ; preparation of suchcompounds of Formula (I) wherein R₃ is C(═Z')H proceed in an analogousfashion from the compound of Formula (2) wherein ═Z' is an aldehydeprotecting group, such as a dimethylacetal or a dioxolane, followed bydeprotection to the aldehyde and subsequent elaboration by standardprocedures known to those of skill in the art to the remaining compoundsof Formula (I) wherein Z' is other than O.

Saponification of the ester moiety of compounds of Formula (I) whereinR₃ is other than COOR₈ and wherein Z is CH₂ COOCH₃ with, e.g., potassiumhydroxide in methanol, provides compounds of Formula (I) wherein R₃ isother than COOR₈ and wherein Z is CH₂ COOH; preparation of suchcompounds of Formula (I) wherein R₃ is COOR₈ proceed in an analogousfashion from the compound of Formula (2) wherein ═Z' is an aldehydeprotecting group, such as a dimethylacetal or a dioxolane, followed bydeprotection to the aldehyde and subsequent elaboration by standardprocedures known to those of skill in the art to the remaining compoundsof Formula (I) wherein R₃ is COOR₈.

Compounds of Formula (I) wherein R₃ is other than C(═Z')H and wherein Zis CH₂ OH may be prepared in a wide variety of ways. For example, withappropriate manipulation of certain chemically sensitive functionalgroups, conversion of the ketone of the compounds of Formula (2) whereinR₁ represents R₁ as defined in relation to Formula (I) or a groupconvertable to R₁ and X and X₃ represents X and X₃ as defined inrelation to Formula (I) or a group convertable to X or X₃ and R₃represents R₃ as defined in relation to Formula (I) or a groupconvertable to R₃ and wherein R₃ is other than C(═Z')H, to thecorresponding olefin by Wittig, Peterson or other olefination reactionsfollowed by, e.g., hydroboration-oxidation; preparation of suchcompounds of Formula (I) wherein R₃ is C(═Z')H proceed in an analogousfashion from the compound of Formula (2) wherein ═Z' is an aldehydeprotecting group, such as a dimethylacetal or a dioxolane, followed bydeprotection to the aldehyde and subsequent elaboration by standardprocedures known to those of skill in the art to the remaining compoundsof Formula (I) wherein Z' is other than O.

Alternatively, compounds of Formula (I) may be obtained by homologationof the ketone of appropriate compounds of Formula (2) by, e.g., ketenethioacetal formation, subsequent hydrolosis to the aldehyde andreduction. Reductive amination with, e.g., ammonium formate and sodiumcyanoborohydride in an alcoholic solvent, rather than reduction of suchhomologated aldehyde intermediates, provides the compounds of Formula(I) wherein R₃ is other than C(═Z')H and Z is CH₂ NH₂ ; preparation ofsuch compounds of Formula (I) wherein R₃ is C(═Z')H proceed in ananalogous fashion from the homologated aldehyde intermediates wherein═Z' is an aldehyde protecting group, such as a dimethylacetal or adioxolane, followed by deprotection to the R₃ aldehyde and subsequentelaboration by standard procedures known to those of skill in the art tothe remaining compounds of Formula (I) wherein Z' is other than O.

It will be recognized that compounds of Formula (I) may exist in twodistinct diastereomeric forms possessing distinct physical andbiological properties; such isomers may be separated by standardchromatographic methods. Such isomers may be independently converted toother compounds of Formula (I) wherein Z is, e.g., CR₈ R₈ OR₁₄, CR₈ R₈OR₁₅, CR₈ R₈ NR₁₃ R₁₄, CR₈ R₈ NS(O)₂ NR₁₃ R₁₄, CR₈ R₈ NS(O)₂ R₇, or CR₈R₈ NR₁₃ C(Y')R₁₄, by any of the wide variety of O and N alkylation oracylation procedures known to those of skill in the art.

For example, with proper manipulation of any chemically sensitivefunctional groups, compounds of Formula (1) wherein NR₁₃ R₁₄ represent aring, such as a 1- or 2-tetrazole, may be derived from reaction of anappropriate compound of Formula (I) wherein Z possesses a leaving group,L, as in CR₈ R₈ L, and L is a mesylate, tosylate, chloride or bromide,with the appropriate metal salt of HNR₁₃ R₁₄, e.g., 5-(R₁₄)-tetrazole;the appropriate compound of Formula (I) wherein Z is mesylate, tosylate,Br or Cl, derived in turn from the appropriate compound of Formula (1)wherein Z is CR₈ R₈ OH. Using similar procedures but with theappropriate metal salt of SR₁₄ or SR₁₅, compounds of Formula (I) whereinZ is CR₈ R₈ SR₁₄ or CR₈ R₈ SR₁₅ may be prepared.

Compounds of Formula (2) may be prepared in turn by the processesdescribed in copending application U.S. Ser. No. 07/862,083 filed 2April 1992.

The following examples are provided to illustrate how to make and usethis invention. These examples are not intended to and should not beviewed as limiting the scope or practice of this invention in any way.

SYNTHETIC EXAMPLES Example 14-Cyano-4-(3-Cyclopentyloxy-4-Methoxyphenyl)cyclohexan-1 -one(Intermediate of the Formula 2)

1a. (3-Cyclopentyloxy-4-methoxyphenyl)acetonitrile

To a solution of 3-cyclopentyloxy-4-methoxybenzaldehyde (20 g, 90.8mmol) in acetonitrile (100 mL) was added lithium bromide (15 g, 173mmol) followed by the dropwise addition of trimethylsilylchloride (17.4mL, 137 mmol). After 15 min, the reaction mixture was cooled to 0° C.,1,1,3,3-tetramethyldisiloxane (26.7 mL, 151 mmol) was added dropwise andthe resulting mixture was allowed to warm to room temperature. Afterstirring for 3 h, the mixture was separated into two layers. The lowerlayer was removed, diluted with methylene chloride and filtered throughCelite. The filtrate was concentrated under reduced pressure, dissolvedin methylene chloride and refiltered. The solvent was removed in vacuoto provide a light tan oil. To a solution of this crudea-bromo-3-cyclopentyloxy-4-methoxytoluene in dimethylformamide (160 mL)under an argon atmosphere was added sodium cyanide (10.1 g, 206 mmol)and the resulting mixture was stirred at room temperature for 18 h, thenpoured into cold water (600 mL) and extracted three times with ether.The organic extract was washed three times with water, once with brineand was dried (potassium carbonate). The solvent was removed in vacuoand the residue was purified by flash chromatography, eluting with 10%ethyl acetate/hexanes, to provide an off-white solid (17.7 g, 84%): m.p.32°-34° C.; an additional quantity (1.3 g) of slightly impure materialalso was isolated.

1b. Dimethyl 4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)pimelate

To a solution of (3-cyclopentyloxy-4-methoxyphenyl)acetonitrile (7 g,30.3 mmol) in acetonitrile (200 mL) under an argon atmosphere was addeda 40% solution of Triton-B in methanol (1.4 mL, 3.03 mmol) and themixture was heated to reflux. Methyl acrylate (27 mL, 303 mmol) wasadded carefully, the reaction mixture was maintained at reflux for 5 hand then cooled. The mixture was diluted with ether, was washed oncewith 1N hydrochloric acid and once with brine, was dried (magnesiumsulfate) and the solvent was removed in vacuo. The solid residue wastriturated with 5% ethanol/hexane to provide a white solid (9 g, 74%):m.p. 81°-82° C.; and additional 1.1 g (9%) was also obtained from thefiltrate. Analysis Calc. for C₂₂ H₂₉ NO₆ : C 65.49, H 7.25, N3.47;found: C 65.47, H 7.11, N 3.49.

1c.2-Carbomethoxy-4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-1-one

To a solution of dimethyl4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)pimelate (5.9 g, 14.6 mmol)in dry 1,2-dimethoxyethane (120 mL) under an argon atmosphere was addedsodium hydride (80% suspension in mineral oil, 1.05 g, 43.8 mmol). Themixture was heated to reflux for 4.5 h, then was cooled to roomtemperature and was stirred for 16 h. Water was added and the reactionmixture was partitioned between ether and acidic water. The organicextract was dried (magnesium sulfate) and the solvent was removed invacuo. The residue was purified by flash chromatography, eluting with3:1 hexanes/ethyl acetate, to provide a white foam (4.9 g, 93%).

Analysis Calc. for C₁₉ H₂₃ NO₃ ·1/4H₂ O: C67.09, H6.84, N3.72; found: C66.92, H6.61, N3.74.

1d. 4-Cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-1-one

A mixture of2-carbomethoxy-4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-1-one(0.80 g, 2.15 mmol), dimethyl sulfoxide (16 mL), water (1 mL) and sodiumchloride (0.8 g) under an argon atmosphere was heated at 140°-145° C.for 5 h. The reaction mixture was cooled and concentrated. The residuewas purified by flash chromatography, eluting with 3:1 hexanes/ethylacetate, to provide a yellow solid. Trituration with hexanes/ethylacetate yielded a white solid (0.52 g, 77%): m.p. 111°-112° C.

Analysis Calc. for C₁₉ H₂₃ NO₃ : C72.82, H7.40, N4.47;found: C72.72, H7.39, N 4.48.

Example 2 Methyl2-[4-cyano-4-(3-cyclpropylmethoxy-4-methoxyphenyl)cyclohexan-1-yl]acetate

3a. Methyl4-cyano-4-(3-cyclpropylmethoxy-4-methoxyphenyl)cyclohexan-1-ylideneacetate

A solution of methydiethylphosphonate (1.2 mL, 6.68 mmol) in ethyleneglycol dimethyl ether (10 mL) was treated with solid sodium hydride(0.22 g, 7.3 mmol, 80% dispersion in mineral oil) at room temperatureunder an argon atmosphere. After stirring for 1.5 h, a solution of4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)cyclohexanone (1.0 g,3.34 mmol) was added and the mixture was allowed to stir for anadditional 3 h. The reaction mixture was partitioned between methylenechloride and water, was extracted twice, was dried (potassium carbonate)and was evaporated to an oil. Purification by flash columnchromatography, eluting with 2:1 hexanes/ethyl acetate, provided an oil(0.48 g, 40%).

Analysis Calc. for C₂₁ H₂₅ NO₄ ·1/8H₂ O: C70.51, H7.12, N3.92; found:C70.36, H7.01, N3.89.

3b. Methyl2-[4-cyano-4-(3-cyclpropylmethoxy-4-methoxyphenyl)cyclohexan-1-yl]acetate

A solution of methyl 4-cyano-4-(3-cyclpropylmethoxy-4-methoxyphenyl)cyclohexan-1-ylidine acetate (0.19 g, 0.52 mmol) in methanol (10 mL) washydrogenated with 10% palladium on carbon at 50 psi for 3 h. Thereaction mixture was filtered through Celite, was washed with methylenechloride and was evaporated. Purification by flash columnchromatography, eluting with 3:1 hexanes/ethyl acetate, provided an oil(0.16 g, 86% ).

Analysis Calc. for C₂₁ H₂₇ NO₄ : C70.56, H7.61, N3.92; found: C70.49, H7.65, N 3.88.

Example 3 cis-[4-Cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)cyclohexan-1 -yl]methanol

A suspension of methyl 2-[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-1-yl]acetate (0.18 g, 0.52 mmol) in ether (2.0 mL) withmethanol (0.025 mL) and lithium borohydride (0.02 g, 0.78 mmol) wasstirred overnight at room temperature under an argon atmosphere. Thereaction mixture was partitioned between methylene chloride and acidicwater, was extracted three times, was dried (magnesium sulfate) and wasevaporated. Purification by flash column chromatography, eluting with1:1 hexanes/ethyl acetate, provided a white solid (0.1 g, 58.5%): m.p.119°-120° C. Analysis Calc. for C₁₉ H₂₅ NO₃ : C72.35, H7.99,N4.44;found: C71.96, H7.90, N 4.33.

Example 4cis-[4-Cyano-4-(3-cyclopropylmethoxy-4-methoxypheny)cyclohexan-1-yl]methylamine

A solution ofcis-[4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)cyclohexan-1-yl]methanol(0.05 g, 0.16 mmol) in tetrahydrofuran (1.2 mL) under an argonatmosphere was treated with triphenylphosphine (0.04 g, 0.16 mmol),phthalimide (0.02 g, 0.16 mmol) and then diethylazodicarboxylate (0.03mL, 0.16 mmol) was added dropwise. The reaction flask was covered withfoil and the mixture was stirred at room temperature for 30 h. Thesolvent was evaporated and the residue was purified by flash columnchromatography, eluting with 2:1 hexanes/ethyl acetate, to provide thephthalimide (0.06 g, 89.7%), which was dissolved in ethanol (0.5 mL)under an argon atmosphere and refluxed with hydrazine hydrate (0.08 mL,0.15 mmol) for 3 h. The reaction was cooled, the precipitate was removedby filtration, the filtrate was applied to a silica column and theproduct was eluted with 95:5 chloroform/methanol to provide an oil (0.3g, 60% ).

Analysis Calc. for C₁₉ H₂₆ N₂ O₃ ·1/4H₂ O: C 71.55, H 8.37, N 8.78;found: C 71.47, H 8.21, N 8.67.

Example 5cis-[4-Cyano-4-(3-cyclopropylmethoxy-4-methoxypheny)cyclohexan-1-yl]methyleneoxide

To a mixture of 80% sodium hydride in mineral oil (0.06 g, 2.00 mmol)and trimethylsulfonium iodide (0.41 g, 2.00 mmol) at room temperatureunder an argon atmosphere was added dropwise dimethylsulfoxide (4 mL)and the reaction mixture was stirred for 0.5 h. A solution of4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl) cyclohexan-1-one (0.50g, 1.67 mmol) in dimethylsulfoxide (2 mL) was added and stirring wascontinued for 45 min. The reaction mixture was quenched with saturatedammonium chloride, was partitioned between ethyl acetate and water, wasdried (magnesium sulfate) and the solvent was removed in vacuo. Theresidue was purified by flash chromatography, eluting with 3:7 ethylacetate/hexanes, to provide a white solid (0.28 g, 53%): m.p. 90°-91° C.

Analysis Calc. for C₁₉ H₂₃ NO₃ ·1/4H₂₀ : C 71.79, H 7.45, N 4.41; found:C 71.97, H 7.33, N 4.36.

A small amount of the trans-isomer (0.09 g, 17%) was also isolated.

Example 6 cis-[4-Cyano-4-(3-cyclopropylmethoxy-4-methoxypheny)-1-hydroxycyclohexan-1-yl]methanol

A mixture ofcis-[4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)cyclohexan-1yl]methyleneoxide(0.14 g, 0.45 retool) and potassium hydroxide (0.02 g, 0.36 mmol) in85:15 dimethylsulfoxide/water (14 mL) under an argon atmosphere washeated at 100°-110° C. for 1.5 h, was cooled, was diluted with water andwas extracted three times with ethyl acetate. The organic extract waswashed four times with water, once with brine, was dried (magnesiumsulfate) and was evaporated. Purification by flash chromatography,eluting with 2% methanol/dichloromethane, provided the cis-isomer as awhite solid (0.09 g, 60%): m.p. 48°-50° C.

Analysis Calc. for C₁₉ H₂₅ NO₄ ·1/8H₂ : C 68.39, H 7.63, N 4.20; found:C 68.23, H 7.59, N 4.13.

Example 7trans-[4-Cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)-1-cyclohexan-1-yl]methyleneoxide

To a mixture of 80% sodium hydride in mineral oil (0.33 g, 11 mmol) andtrimethylsulfoxonium iodide (1.69 g, 7.67 mmol) at room temperatureunder an argon atmosphere was added dropwise dimethylsulfoxide (12 mL)and the reaction mixture was stirred for 30 min. A solution of4-cyano-4-(3-cyclopropylmethoxy-3-methoxyphenyl)-cyclohexan-1-one (2.00g, 6.68 mmol) in dimethylsulfoxide (5 mL) was added and stirring wascontinued for 30 min. The reaction mixture was quenched with saturatedammonium chloride, was partitioned between ethyl acetate and water, wasdried (magnesium sulfate) and the solvent was removed in vacuo. Theresidue was purified by flash chromatography, eluting with 1:3 ethylacetate/hexanes, to provide a colorless oil (1.42 g, 68%).

Analysis Calc. for C₁₉ H₂₃ NO₃ ·H₂ O: C 68.86, H 7.30, N 4.23; found: C69.22, H 7.11, N 4.17. Starting material was also recovered (0.6 g,30%).

Example 8 trans-[4-Cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)-1-hydroxycyclohexan-1-yl]methanol

A mixture oftrans-[4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)-cyclohexan-1-yl]methyleneoxide(1.31 g, 4.18 mmol) and potassium hydroxide (0.14 g, 2.5 mmol) in 85:15dimethylsulfoxide/water (140 mL) under an argon atmosphere was heated at100°-110° C. for 1 h, was cooled, was diluted with water and wasextracted three times with ethyl acetate. The organic extract was washedfive times with water, was dried (magnesium sulfate) and was evaporated.Purification by flash chromatography, eluting with 3.5:96.5methanol/dichloromethane, provided the trans-isomer as a sticky whitesolid: m.p. 38°-42° C. (0.96 g, 69% ).

Analysis Calc. for C₁₉ H₂₅ NO₄ : C 68.86, H 7.60, N 4.23; found: C68.96, H 7.62, N 4.03.

METHODS OF TREATMENT

In order to use a compound of Formula (I) or a pharmaceuticallyacceptable salt thereof may be used neat though a preferred technique isto present them with a carrier/diluent accordance with standardpharmaceutical practice. Any formulation compatible with the chosenmethod of delivery and the stafility of the compound may be used. Oneskilled in the an will be able to select and prepare an acceptableformulation in accordance with standard practices in the field of theformulary arts.

The compounds of Formula (I) or may be administered orally (when activeby this route), oral, intravenous, intraperitoneal, and intramuscularadministration, topically, parenterally, or by inhalation inconventional dosage forms prepared by combining such agent with standardpharmaceutical carriers according to conventional procedures in anamount sufficient to produce the desired therapeutic activity.

The amount of a compound of Formula (I) required for therapeutic effecton topical administration will, of course, vary with the compoundchosen, the nature and seventy of the condition and the animalundergoing treatment, and is ultimately at the discretion of thephysician.

The daily dosage regimen for oral administration is suitably about 0.001mg/kg to 100 mg/kg, preferably 0.01 mg/Kg to 40 mg/Kg, of a compound ofFormula (I) or a pharmaceutically acceptable salt thereof calculated asthe free base. The active ingredient may be administered from 1 to 6times a day, sufficient to exhibit activity.

UTILITY EXAMPLES Example A Inhibitory effect of compounds of Formula (I)on in vitro TNF production by human monocytes

The inhibitory effect of compounds of Formula (I) on in vitro TNFproduction by human monocytes may be determined by the protocol asdescribed in Badger et al., EPO published Application 0 411 754 A2, Feb.6, 1991, and in Hanna, WO 90/15534, Dec. 27, 1990.

Example B

Two models of endotoxic shock have been utilized to determine in vivoTNF activity for the compounds of Formula (I). The protocol used inthese models is described in Badger et al., EPO published Application 0411 754 A2, Feb. 6, 1991, and in Hanna, WO 90/15534, Dec. 27, 1990.

The exemplified compounds herein demonstrated a positive in vivoresponse in reducing serum levels of TNF induced by the injection ofendotoxin.

Example C Isolation of PDE Isozymes

The phosphodiesterase inhibitory activity and selectivity of thecompounds of Formula (I) can be determined using a battery of fivedistinct PDE isozymes. The tissues used as sources of the differentisozymes are as follows: 1) PDE Ib, porcine aorta; 2) PDE Ic, guinea-pigheart; 3) PDE III, guinea-pig heart; 4) PDE IV, human monocyte; and 5)PDE V (also called "Ia"), canine trachealis. PDEs Ia, Ib, Ic and III arepartially purified using standard chromatographic techniques [Torphy andCieslinski, Mol. Pharmacol., 37:206-214, 1990]. PDE IV is purified tokinetic homogeneity by the sequential use of anion-exchange followed byheparin-Sepharose chromatography [Torphy et al., J. Biol. Chem.,267:1798-1804, 1992].

Phosphodiesterase activity is assayed as described in the protocol ofTorphy and Cieslinski, Mol. Pharmacol., 37:206-214, 1990. Positive IC₅₀'s in the nanomolar to μM range for compounds of the workings examplesdescribed herein for Formula (I) have been demonstrated.

Example D

The ability of selected PDE IV inhibitors to increase cAMP accumulationin intact tissues is assessed using U-937 cells, a human monocyte cellline that has been shown to contain a large amount of PDE IV. To assessthe activity of PDE IV inhibition in intact cells, nondifferentiatedU-937 cells (approximately 10⁵ cells/reaction tube) were incubated withvarious concentrations (0.01-1000 μM) of PDE inhibitors for one minuteand 1 μM prostaglandin E2 for an additional four minutes. Five minutesafter initiating the reaction, cells were lysed by the addition of 17.5%perchloric acid, the pH was neutralized by the addition of 1M potassiumcarbonate and cAMP content was assessed by RIA. A general protocol forthis assay is described in Brooker et al., Radioimmunassay of cyclic AMPand cyclic GMP., Adv. Cyclic Nucleotide Res., 10:1-33, 1979. Thecompounds of the working examples as described herein for Formula (I)have demonstrated a positive EC ₅₀ s in the μM range in the above assay.

No toxic effects are expected when these compounds are administered inaccordance with the present invention.

What is claimed is:
 1. A compound of Formula (I): ##STR5## wherein: R₁is --(CR₄ R₅)_(n) C(O)O(CR₄ R₅)_(m) R₆, --(CR₄ R₅)_(n) C(O)NR₄ (CR₄R₅)_(m) R₆,--(CR₄ R₅)_(n) O(CR₄ R₅)_(m) R₆, or --(CR₄ R₅)_(r) R₆ whereinthe alkyl moieties may be optionally substituted with one or morehalogens;m is 0 to 2; n is 1 to 4; r is 0 to 6; R₄ and R₅ areindependently selected from hydrogen or a C₁₋₂ alkyl; R₆ is hydrogen,methyl, hydroxyl, aryl, halo substituted aryl, aryloxyC₁₋₁₃ alkyl, halosubstituted aryloxyC₁₋₁₃ alkyl, indenyl, indenyl, C₇₋₁₁ polycycloalkylC₃₋₆ cycloalkyl, or a C₄₋₆ cycloalkyl containing one or two unsaturatedbonds, wherein the cycloalkyl moiety may be optionally substituted by 1to 3 methyl groups or one ethyl group; provided that:a) when R₆ ishydroxyl, then m is 2; or b) when R₆ is hydroxyl, then r is 2 to 6; orc) when n is 1 and m is 0, then R₆ is other than H in --(CR₄ R₅)_(n)O(CR₄ R₅)_(m) R₆ ; X is YR₂, halogen, nitro, NR₄ R₅, or formyl amine; Yis O; m' is a number having a value of 0, 1, or 2 ; X₂ is O or NR₈ ; X₃is hydrogen or X; R₂ is independently selected from --CH₃ or --CH₂ CH₃optionally substituted by 1 or more halogens; s is 0 to 4; R₃ is CN; Zis CR₈ R₈ OR₁₄, CR₈ R₈ OR₁₅, CR₈ R₈ SR14, CR₈ R₈ SR₁₅, CR₈ R₈ S(O)_(m')R₇, CR₈ R₈ NR₁₀ R₁₄, CR₈ R₈ NR₁₀ S(O)₂ NR₁₀ R₁₄, CR₈ R₈ NR₁₀ S(O)₂ R₇,CR₈ NR₁₀ C(Y')R₁₄, CR₈ R₈ NR₁₀ C(O)OR₇, CR₈ R₈ NR₁₀ C(Y')NR₁₀ R₁₄, CR₈R₈ NR₁₀ C(NCN)NR₁₀ R₁₄, CR₈ R₈ NR₁₀ C(CR₄ NO₂)NR₁₀ R₁₄, CR₈ R₈ NR₁₀C(NCN)SR₉, CR₈ R₈ NR₁₀ C(CR₄ NO₂)SR₉, CR₈ R₈ C(O)OR₁₄, CR₈ R₈ C(Y')NR₁₀R₁₄, CR₈ R₈ C(NR₁₀) NR₁₀ R₁₄, CR₈ R₈ CN, CR₈ R₈ (tetrazolyl), CR₈ R₈(imidazolyl), CR₈ R₈ (imidazolidinyl), CR₈ R₈ (pyrazolyl), CR₈ R₈(thiazolyl), CR₈ R₈ (thiazolidinyl), CR₈ R₈ (oxazolyl), CR₈ R₈(oxazolidinyl), CR₈ R₈ (triazolyl), CR₈ R₈ (isoxazolyl), CR₈ R₈(oxadiazolyl), CR₈ R₈ (thiadiazolyl), CR₈ R₈ (morpholinyl), CR₈ R₈(piperidinyl), CR₈ R₈ (piperazinyl), CR₈ R₈ (pyrrolyl), CR₈ R₈C(NOR₈)R₁₄, CR₈ R₈ C(NOR₁₄)R₈, CR₈ R₈ NR₁₀ C(NR₁₀)SR₉, CR₈ R₈ NR₁₀C(NR₁₀)NR₁₀ R₁₄, CR₈ R₈ NR₁₀ C(O)C(O)NR₁₀ R₁₄, or CR₈ R₈ NR₁₀C(O)C(O)OR₁₄ ; Y' is O; R₇ is --(CR₄ R₅)_(q) R₁₂ or C₁₋₆ alkyl whereinthe R₁₂ or C₁₋₆ alkyl group is optionally substituted one or more timesby C₁₋₂ alkyl optionally substituted by one to three fluorines, --F,--Br, --Cl, --NO₂, --NR₁₀ R₁₁, --C(O)R₈, --C(O)OR₈, --OR₈, --CN,--C(O)NR₁₀ R₁₁, --OC(O)NR₁₀ R₁₁, --OC(O)R₈, --NR₁₀ C(O)NR₁₀ R₁₁, --NR₁₀C(O)R₁₁, --NR₁₀ C(O)OR₉, --C(NR₁₀)NR₁₀ R₁₁, --C(NCN)NR₁₀ R₁₁,--C(NCN)SR₉, --NR₁₀ C(NCN)SR₉, --NR₁₀ C(NCN)NR₁₀ R₁₁, --NR ₁₀ S(O)₂ R₉,--S(O)_(m') R₉, --NR₁₀ C(O)C(O)NR₁₀ R₁₁, NR₁₀ C(O)C(O)R₁₀ ; q is 0, 1,or 2; R₁₂ is C₃₋₇ cycloalkyl, (2-, 3- or 4-pyridyl), pyrimidyl,pyrazolyl, (1- or 2-imidazolyl), thiazolyl, triazolyl, pyrrolyl,piperazinyl, piperidinyl, morpholinyl, furanyl, (2- or 3-thienyl), (4-or 5-thiazolyl), quinolinyl, naphthyl, or phenyl; R₈ is independentlyselected from hydrogen or R₉ ; R_(8'), is R₈ or fluorine; R₉ is C₁₋₄alkyl optionally substituted by one to three fluorines; R₁₀ is OR₈ orR₁₁ ; R₁₁ is hydrogen, or C₁₋₄ alkyl optionally substituted by one tothree fluorines; or when R₁₀ and R₁₁ are as NR₁₀ R₁₁ they may togetherwith the nitrogen form a 5 to 7 membered ring optionally containing atleast one additional heteroatom selected from O, N, or S; R₁₄ ishydrogen or R₇ ; R₁₅ is C(O)R₁₄, C(O)NR₄ R₁₄, S(O)₂ R₇, or S(O)₂ NR₄ R₁₄; or the pharmaceutically acceptable salts thereof.
 2. A compound ofclaim 1 whereinR₁ is --CH₂ -cyclopropyl, cyclopentyl, methyl or CF₂ H;R₃ is CN; X is YR₂ ; Y is O; X₂ is oxygen; and X₃ is hydrogen.
 3. Acompound according to claim 2 which is:methyl2-[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-1-yl]acetate;cis-[4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)cyclohexan-1-yl]methanol;cis-[4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)cyclohexan-1-yl]methylamine;cis-[4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)cyclohexan-1,1-diyl]oxirane;cis-[4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)-1-hydroxycyclohexan-1-yl]methanol;trans-[4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)cyclohexan-1,1-diyl]oxirane;ortrans-[4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)-1-hydroxycyclohexan-1-yl]methanol.4. A pharmaceutical composition comprising a compound of Formula (I)according to claim 1 and a pharmaceutically acceptable excipient.
 5. Amethod for treating an allergic or inflammatory disease which methodcomprises administering to a subject in need thereof an effective amountof a compound of Formula (I) according to claim 1 alone or incombination with a pharmaceutically acceptable excipient.